[unreadable] The exponential increase in sequence data from diverse organisms continues to enhance the power of sequence comparison for understanding protein function. For over a decade, our protein alignment tools based on conserved regions of proteins (blocks) have facilitated functional analysis. These include the Blocks database, BLOSUM amino acid substitution matrices, position based searching strategies, PSSM and weighting methods, and a PCR primer design strategy for isolating distantly related homologs. Our tools are tightly integrated for web-based use by nonexperts in the general biological community. In addition, we have promulgated tools for setting up protein family web sites by communities of researchers. [unreadable] [unreadable] Most recently, we introduced position-based methods for predicting deleterious mutations and variants in organisms ranging from bacteria to humans. We have also introduced a new reverse genetics strategy, called TILLING (for Targeting Induced Local Lesions IN Genomes). TILLING provides allelic series of point mutations in genes of interest, mostly missense mutations, which are analyzed using blocks-based tools that we have developed. [unreadable] [unreadable] We propose to update and expand the Blocks Database, which is a central component of our system, and maintain blocks-based tools for searching and for displaying conserved regions and motif and for PCR primer design. We also propose to maintain tools for predicting damaging amino acid changes in proteins, for choosing regions of genes to be TILLed and for displaying TILLING results and for support of protein family web sites. These various components will be packaged to facilitate updates and local implementations. [unreadable] [unreadable]